Consumer medicine information

Femoston-Conti

Estradiol; Dydrogesterone

BRAND INFORMATION

Brand name

Femoston-Conti

Active ingredient

Estradiol; Dydrogesterone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Femoston-Conti.

SUMMARY CMI

FEMOSTON®-CONTI

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. When I must not use FEMOSTON-CONTI?

Do not use FEMOSTON-CONTI or other estrogens, with or without a progestogen to prevent heart attacks, stroke or dementia.

2. Why am I using FEMOSTON-CONTI?

FEMOSTON-CONTI contains the active ingredients estradiol and dydrogesterone. It is used to relieve the discomfort many women feel during and after the menopause. It also helps to prevent thinning of the bones, which can cause fractures. It is used by women who still have a uterus (womb). For more information, see Section 2. Why am I using FEMOSTON-CONTI? in the full CMI.

3. What should I know before I use FEMOSTON-CONTI?

Do not use if you have ever had an allergic reaction to any medicine containing estradiol or dydrogesterone or any of the ingredients listed at the end of the CMI. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 3. What should I know before I use FEMOSTON-CONTI? in the full CMI.

4. What if I am taking other medicines?

Some medicines may interfere with FEMOSTON-CONTI and affect how it works. A list of these medicines is in Section 4. What if I am taking other medicines? in the full CMI.

5. How do I use FEMOSTON-CONTI?

6. What should I know while using FEMOSTON-CONTI?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using FEMOSTON-CONTI.
  • If you become pregnant while you are taking this medicine, tell your doctor or pharmacist immediately.
  • See your doctor at least once a year for a check-up.
  • Check your breasts each month and report any changes promptly to your doctor.
  • Include foods that are good sources of calcium and Vitamin D in your daily diet and exercise regularly.
Things you should not do
  • Do not use this medicine to treat any other complaints unless your doctor or pharmacist tells you to.
  • Do not give this medicine to anyone else, even if they have the same condition as you.
  • Do not stop taking FEMOSTON-CONTI, or change the dosage, without checking with your doctor.
Looking after your medicine
  • Keep your tablets in the pack until it is time to take them.
  • Keep the medicine in a cool, dry place where the temperature stays below 30°C.

For more information, see Section 6. What should I know while using FEMOSTON-CONTI? in the full CMI.

7. Are there any side effects?

Tell your doctor if you notice any irregular vaginal bleeding, painful or swollen breasts, period-like pain, vaginal itching or fluid discharge, swelling of the lower legs, ankles, fingers or abdomen, nausea, abdominal cramps, vomiting, heartburn, wind, diarrhoea, headache, migraine, rise in blood pressure, dizziness, depression, nervousness, changes in mood, difficulty sleeping, worsening of epilepsy, back pain, change in sex drive, weight change, acne, itchy or dry skin, skin discolouration.
Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you have signs of allergic reaction, sudden severe headache, sudden loss of coordination, blurred vision or sudden loss of vision, bulging of eyeball, slurred speech, numbness in an arm or leg, painful swelling in the calves or thighs, chest pain, difficulty breathing, coughing blood, pain or tenderness in the abdomen, a yellow colour to the skin or eyes, itching, dark coloured urine or light coloured bowel motions. For more information, including what to do if you have any side effects, see Section 7. Are there any side effects? in the full CMI.

WARNING: Do not use FEMOSTON-CONTI or other estrogens, with or without a progestogen to prevent heart attacks, stroke or dementia.



FULL CMI

FEMOSTON®-CONTI

Active ingredient(s): estradiol and dydrogesterone


Consumer Medicine Information (CMI)

This leaflet provides important information about using FEMOSTON-CONTI. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using FEMOSTON-CONTI.

Where to find information in this leaflet:

1. When I must not use FEMOSTON-CONTI?
2. Why am I using FEMOSTON-CONTI?
3. What should I know before I use FEMOSTON-CONTI?
4. What if I am taking other medicines?
5. How do I use FEMOSTON-CONTI?
6. What should I know while using FEMOSTON-CONTI?
7. Are there any side effects?
8. Product details

1. When I must not use FEMOSTON-CONTI?

Do not use FEMOSTON-CONTI or other estrogens, with or without a progestogen to prevent heart attacks, stroke or dementia.

A study called the Women's Health Initiative indicated increased risk of stroke, breast cancer, and blood clots in the legs or lungs in women receiving treatment with a product containing conjugated estrogens 0.625 mg and the progestogen medroxyprogesterone acetate (MPA). The researchers stopped the study after 5 years when it was determined the risks were greater than the benefits in this group.

Talk regularly with your doctor about whether you still need treatment with FEMOSTON-CONTI.

Treatment with estrogens, with or without progestogens should be used at the lowest effective dose and for the shortest period of time.

2. Why am I using FEMOSTON-CONTI?

FEMOSTON-CONTI contains the hormones estradiol and dydrogesterone. FEMOSTON-CONTI is a type of treatment called hormone replacement therapy (HRT).

FEMOSTON-CONTI helps to relieve the discomfort many women feel during and after the menopause. It also helps to prevent thinning of the bones (osteoporosis), which can cause fractures. FEMOSTON-CONTI is used by women who still have a uterus (womb).

Menopause may be natural or occur after surgery or medical treatment.

HRT should not be used for the long-term maintenance of general health or to prevent heart disease.

FEMOSTON-CONTI is not a contraceptive (birth control) and will not prevent pregnancy or restore fertility. Since pregnancy may be possible early in the menopause while you are still having menstrual periods, you should ask your doctor to suggest another (non-hormonal) method of birth control.

How it works

Estradiol is a natural female sex hormone called an estrogen. It is the same hormone that your ovaries were producing before the menopause. Dydrogesterone is a hormone called a progestogen. It has effects like the female hormone, progesterone, which your ovaries also produced before the menopause.

Menopause generally occurs between the ages of 45 and 55, because your body's production of estrogen decreases. This can cause unpleasant symptoms such as a feeling of warmth in the face, neck and chest, "hot flushes" (sudden intense feelings of heat and sweating throughout the body), sleep problems, irritability and depression. Some women also have problems with urine control or with dryness of the vagina causing discomfort during or after sex. Estrogens can be given to reduce these symptoms.

After the age of 40, and especially after the menopause, some women develop osteoporosis. This is a thinning of the bones that makes them weaker and more likely to break, especially the bones of the spine, hip and wrist. The risk of osteoporosis is increased by lack of estrogen. Estrogens can be given to reduce this risk if other treatments are not suitable.

Women who still have a uterus must take both estrogen and progestogen as part of HRT. This is because estrogen stimulates the growth of the lining of the uterus (called the endometrium). Before menopause this lining is removed during your period through the action of your natural progestogen. After menopause, taking estrogen on its own as HRT may lead to irregular bleeding and to a disorder called endometrial hyperplasia. Progestogens such as dydrogesterone help to protect the lining of the uterus from developing this disorder.

Ask your doctor if you have any questions about why it has been prescribed for you.

Your doctor may have prescribed it for another purpose.

This medicine is not addictive.

3. What should I know before I use FEMOSTON-CONTI?

Warnings

HRT should only be used if you have been fully informed of the risks.

The decision to use HRT should be based on your symptoms and health, and made after a careful medical evaluation.

Do not use FEMOSTON-CONTI if:

  • you have an allergy to any medicine containing estradiol or dydrogesterone, or any of the ingredients listed at the end of this leaflet
    - Some symptoms of an allergic reaction include skin rash, itching, shortness of breath or swelling of the face, lips or tongue, which may cause difficulty in swallowing or breathing.

Do not take FEMOSTON-CONTI if you have/have experienced:

  • A hysterectomy
  • Cancer of the breast or uterus (endometrium) or any other estrogen or progestogen dependent cancer.
  • Blood clots. Painful inflammation or blockages of a blood vessel in the legs, lungs, brain or heart.
  • Any condition that increases the tendency for you to get blood clots
  • Untreated endometrial hyperplasia (the lining of the uterus becomes too thick)
  • Abnormal vaginal bleeding that has not been investigated
  • Severe liver disease
  • A condition called porphyria

If you are not sure whether any of the above conditions apply to you, your doctor can advise you.

Do not give FEMOSTON-CONTI to a child under the age of 18 years.

Safety and effectiveness in children younger than 18 years have not been established.

You must stop taking FEMOSTON-CONTI 4 weeks before certain types of surgery.

Tell your doctor or pharmacist if you have any allergies to any other medicines, foods, preservatives or dyes.

You must have a thorough medical check-up before starting HRT for the first time or recommencing HRT.

Tell your doctor if you have or have had any of the following medical conditions:

  • a family history of breast cancer
  • nodules, lumps or cysts in your breasts or any other benign breast condition (not cancer)
  • fibroids or other benign tumours of the uterus (not cancer)
  • ovarian cancer
  • unusual or irregular bleeding or spotting from the vagina
  • endometriosis
  • high blood pressure
  • liver problems
  • cholestatic jaundice (obstruction of bile)
  • kidney problems
  • heart problems
  • diabetes
  • migraine or severe headache
  • asthma
  • epilepsy
  • systemic lupus erythematosus
  • gall stones or gall bladder disease
  • a high level of triglycerides (fats) in the blood
  • high or low levels of calcium in the blood.
  • Abnormal vision
  • Hypothyroidism
  • Otosclerosis - hearing loss due to a problem with the bones in the ear

Tell your doctor if you are likely to have an increased risk of developing blood clots in your blood vessels.

The risk increases as you get older and it may also be increased if:

  • anyone in your immediate family has ever had blood clots in the blood vessels of the legs or lungs
  • you are overweight
  • you have varicose veins
  • you have a disorder called systemic lupus erythematosus (SLE).

Your doctor will advise you whether or not to take FEMOSTON-CONTI, or if you need to adjust the dose, or adapt your treatment.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 7. Are there any side effects?

Pregnancy and breastfeeding

Do not take this medicine if you are pregnant. Discuss with your doctor if you are planning on becoming pregnant.

Do not breastfeed if you are taking this medicine.

4. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and FEMOSTON-CONTI may interfere with each other. These include:

  • herbal medicines containing St John's wort
  • some medicines for epilepsy such as phenytoin, phenobarbital, carbamazepine and lamotrigine
  • some antibiotics and antivirals such as rifampicin and ritonavir
  • some medicines with a narrow therapeutic index such as tacrolimus, ciclosporin, fentanyl and theophylline

These medicines may be affected by FEMOSTON-CONTI, or may affect how well it works. You may need to use different amounts of your medicine, or take different medicines.

Your doctor or pharmacist has more information on medicines to be careful with or to avoid while taking FEMOSTON-CONTI.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect FEMOSTON-CONTI.

5. How do I use FEMOSTON-CONTI?

Follow all directions given to you by your doctor carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions on the box, ask your doctor or pharmacist for help.

When to start taking it

If you have not had a period for 12 months or more, you can start FEMOSTON-CONTI immediately.

How much to take

  • The usual dose is one tablet daily.

How to take it

  • Swallow the tablets whole with a glass of water.

When to take it

It does not matter if you take this medicine before or after food.

Take FEMOSTON-CONTI at about the same time each day.

Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

The tablets are labelled with the days of the week to help you make sure you are taking your tablets every day.

You should start with a tablet labelled according to the day of the week.

You should start each new pack the day after you have finished the old pack. Do not leave a gap between packs.

If changing from sequential HRT, you should commence at the end of the estrogen plus progestogen phase of the sequential therapy without a break.

How long to take it

Your doctor can advise you how long you may need to take FEMOSTON-CONTI.

Your doctor can discuss the risks and benefits of long-term treatment with HRT. Some recent studies have shown that women using HRT have a small increase in breast cancer risk after several years of use. The risk increases with the length of HRT use.

Recent studies have also shown that HRT is associated with a small increase in the risk of strokes, blood clots, including clots in the lungs. The studies also showed that the risk of hip fractures and bowel cancer may be reduced.

Continue taking FEMOSTON-CONTI for as long as your doctor recommends.

If you forget to use FEMOSTON-CONTI

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

A slight vaginal bleeding, like an irregular period, may occur.

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

Do not take a double dose to make up for the dose that you missed.

If you have forgotten to take more than one tablet, discuss this with your doctor.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering when to take your medicine, ask your pharmacist for advice.

If you use too much FEMOSTON-CONTI

If you think that you or anyone else may have used too much FEMOSTON-CONTI, you may need urgent medical attention. Symptoms such as nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue, and withdrawal bleeding could occur in cases of overdosing.

You should immediately:

  • phone the Poisons Information Centre
    (Australia telephone 13 11 26 for advice, or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

6. What should I know while using FEMOSTON-CONTI?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking FEMOSTON-CONTI.

Tell any other doctors, dentists and pharmacists who treat you that you are taking this medicine.

Tell your doctor that you are using FEMOSTON-CONTI well in advance of any expected hospitalisation or surgery. If you go to hospital unexpectedly, tell the doctor who admits you that you are using it.

The risk of developing blood clots in your blood vessels may be temporarily increased after surgery, serious injury or having to stay in bed for a long period of time. If possible, FEMOSTON-CONTI should be stopped at least 4 weeks before surgery and it should not be restarted until you are fully mobile.

If you become pregnant while you are taking this medicine, tell your doctor or pharmacist immediately.

See your doctor at least once a year for a check-up. Some women will need to go more often. Your doctor will check:

  • your breasts and order a mammogram at regular intervals
  • your uterus and cervix and do a pap smear at regular intervals
  • your blood pressure and cholesterol level

Check your breasts each month and report any changes promptly to your doctor.

Your doctor or nurse can show you how to check your breasts properly.

If you notice any changes to your breasts, see your doctor.

Include foods that are good sources of calcium and Vitamin D in your daily diet and exercise regularly. Calcium, Vitamin D and exercise may help prevent thinning of the bones. Your doctor can advise you on which foods and types of exercise are best for you.

Things you should not do

  • Do not use this medicine to treat any other complaints unless your doctor or pharmacist tells you to.
  • Do not give this medicine to anyone else, even if they have the same condition as you.
  • Do not stop taking FEMOSTON-CONTI, or change the dosage, without checking with your doctor.

Looking after your medicine

  • Keep your tablets in the pack until it is time to take them.
    If you take the tablets out of the box or the blister pack they may not keep well.
  • Keep the medicine in a cool, dry place where the temperature stays below 30°C.
  • Keep it where children cannot reach it.
    A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

When to discard your medicine

If your doctor or pharmacist tells you to stop taking this medicine, or the medicine has passed its expiry date, ask your pharmacist what to do with any that are left over.

Getting rid of any unwanted medicine

Do not take it after the expiry date printed on the pack or if the packaging is damaged or shows signs of tampering.

If it has expired or is damaged return it to your pharmacist for disposal.

7. Are there any side effects?

Tell your doctor as soon as possible if you do not feel well while you are taking FEMOSTON-CONTI.

It helps most people, but it may have unwanted side effects in a few people. All medicines have some unwanted side effects. Sometimes they are serious, but most of the time they are not. You may need medical attention if you get some of the side-effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Less serious side effects

Less serious side effectsWhat to do
  • irregular vaginal bleeding or spotting (if bleeding is heavy, check with your doctor as soon as possible)
  • tender, painful or swollen breasts
  • period-like pain
  • vaginal itching, inflammation or fluid discharge
  • swelling of the lower legs, ankles, fingers or abdomen due to fluid retention
  • nausea (feeling sick), abdominal cramps, vomiting, heartburn, wind, diarrhoea
  • headache, migraine
  • rise in blood pressure
  • weakness or dizziness
  • depression, nervousness, rapid changes in mood, difficulty sleeping
  • worsening of a condition called epilepsy
  • back pain
  • change in sex drive
  • weight gain or weight loss
  • acne, itchy or dry skin, skin discolouration.
Tell your doctor if you notice any of these common and uncommon side effects of your medicine. They are usually mild and short-lived.

Serious side effects

Serious side effectsWhat to do
  • signs of allergic reaction such as a rash or hives on the skin, swelling of the face, lips, tongue or other parts of the body, shortness of breath or troubled breathing
  • sudden severe headache
  • sudden loss of coordination
  • blurred vision or sudden loss of vision, bulging of eyeball
  • slurred speech
  • numbness or tingling in an arm or leg
  • painful swelling in the calves or thighs
  • chest pain
  • difficulty breathing
  • coughing blood
  • pain or tenderness in the abdomen, which may be accompanied by fever, loss of appetite, nausea and vomiting
  • a yellow colour to the skin or eyes, itching, dark coloured urine or light coloured bowel motions.
Tell your doctor immediately or go to the Emergency Department at your nearest hospital if you notice any of these very serious side effects. These side effects are rare.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

8. Product details

This medicine is only available with a doctor's prescription.

What FEMOSTON-CONTI contains

Active ingredient
(main ingredient)
Femoston-Conti contains 1 mg estradiol (as hemihydrate) and 5 mg dydrogesterone as the active ingredients.
Other ingredients
(inactive ingredients)
  • lactose monohydrate
  • hypromellose
  • maize starch
  • colloidal anhydrous silica
  • magnesium stearate
  • The colour ingredients used in FEMOSTON-CONTI is Opadry OY-8734 orange (ARTG PI No. 4164).
Potential allergensThe tablets contain sugars as lactose.

Do not take this medicine if you are allergic to any of these ingredients.

What FEMOSTON-CONTI looks like

FEMOSTON-CONTI contains:

28 round, salmon-coloured tablets, each containing 1 mg estradiol and 5 mg dydrogesterone bearing the inscriptions "379" on one side.

(AUST R 78654)

FEMOSTON-CONTI is available in packs of 28 tablets.

Who distributes FEMOSTON-CONTI

Viatris Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.viatris.com.au
Phone: 1800 274 276

This leaflet was prepared in November 2023.

FEMOSTON®-CONTI is a Viatris company trade mark

FEMOSTON-CONTI_cmi\Nov23/00

Published by MIMS January 2024

BRAND INFORMATION

Brand name

Femoston-Conti

Active ingredient

Estradiol; Dydrogesterone

Schedule

S4

 

1 Name of Medicine

Estradiol (as hemihydrate) and dydrogesterone.

2 Qualitative and Quantitative Composition

Femoston-Conti tablets are immediate-release, film-coated tablets for oral use containing 1 mg estradiol (as hemihydrate) and 5 mg dydrogesterone.

Excipients with known effect.

Sugars as lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Round, biconvex, salmon-coloured, film-coated tablets each containing 1 mg estradiol (as hemihydrate) and 5 mg dydrogesterone bearing the inscriptions "379" on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Hormone replacement therapy (HRT) in estrogen deficiency associated with natural or artificial menopause in women with an intact uterus. Prevention of postmenopausal bone mineral density loss in women.
For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration should be used with the goal being short-term use (see Section 4.2 Dose and Method of Administration; Section 5.1 Pharmacodynamic Properties, Clinical trials).
When prescribed solely for the prevention of postmenopausal bone mineral density loss, therapy should only be prescribed for women who are at high risk of osteoporosis and future fracture and who are intolerant of, or contraindicated for nonestrogen products approved for prevention of osteoporosis. Lifestyle modifications and the risk benefit profile of Femoston-Conti should be taken into careful consideration and discussed with the patient, to allow the patient to make an informed decision prior to prescribing (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).

4.2 Dose and Method of Administration

One tablet administered orally daily without interruption. When all the tablets in the pack have been taken, another pack is started without interruption (see Section 4.1 Therapeutic Indications; Section 4.4 Special Warnings and Precautions for Use for treatment duration advice).
If a dose has been forgotten, it should be taken as soon as possible. If more than 12 hours have elapsed, treatment should be continued with the next tablet without taking the forgotten tablet. The likelihood of breakthrough bleeding or spotting may be increased.
Women experiencing a natural menopause should commence treatment with Femoston-Conti 12 months after their last natural menstrual bleed. For surgically induced menopause, treatment may start immediately. Femoston-Conti is intended to prevent stimulation of the endometrium in postmenopausal women, usually resulting in amenorrhoea.

Changing from sequential HRT.

Patients changing from sequential HRT preparations, such as Femoston 1/10 mg or 2/10 mg, to Femoston-Conti should do so at the end of the estrogen plus progestogen phase of the sequential therapy, without a tablet free interval.
Femoston-Conti should normally be used only in women more than 12 month postmenopause. If the menopausal status is not known (e.g. because of previous use of sequential HRT or oral combination contraceptives) the endogenous estrogen may still be high. This could result in unpredictable bleeding patterns, especially in the first few cycles.

Prevention of bone mineral density loss.

Protection appears to be effective for as long as treatment continues, however data on estrogen therapy beyond 10 years are limited. A careful reappraisal of the risk benefit ratio should be undertaken before treatment for longer than 5-10 years. For long-term use, see Section 4.4 Special Warnings and Precautions for Use.
The mainstays for decreasing the risk of postmenopausal osteoporosis are weight bearing exercise, adequate calcium and vitamin D intake, and when indicated, pharmacological therapy. Postmenopausal women require an adequate daily intake of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation may also be required to ensure adequate daily intake in postmenopausal women.

4.3 Contraindications

Women who have had a hysterectomy.
Known or suspected carcinoma of the breast, endometrium or other estrogen dependent neoplasia.
Known or suspected progestogen dependent neoplasms.
Untreated endometrial hyperplasia.
Active or chronic liver disease or a history of liver disease where the liver function tests have failed to return to normal.
Cerebrovascular accident or a past history of the condition associated with previous estrogen use.
Previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism) or cerebrovascular accident.
Known thrombophilic disorders (e.g. protein C, protein S or antithrombin deficiency, see Section 4.4 Special Warnings and Precautions for Use).
Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction).
Abnormal genitourinary tract bleeding of unknown aetiology.
Porphyria.
Known or suspected pregnancy.
Lactation.
Known hypersensitivity to any ingredients contained in Femoston-Conti tablets.

4.4 Special Warnings and Precautions for Use

The benefits and risks of estrogen/ progestogen therapy must always be carefully weighed including consideration of the emergence of risks as therapy continues.

Medical examination/ follow-up.

Before initiating or reinstituting therapy, a complete medical and family history should be taken and a physical examination performed. Pretreatment and subsequent physical examinations should include special reference to blood pressure, breasts, abdomen and pelvic organs. Mammography is advisable. Patients who are being or have previously been treated with unopposed estrogens should be examined with special care to exclude endometrial stimulation before commencing Femoston-Conti therapy.
As a general rule, hormone replacement therapy (HRT) should not be prescribed for longer than one year without another physical examination including gynaecological examination being performed. Women on HRT should have regular breast examinations, and regular mammography (every 1-2 years). Women should be advised what changes in their breasts should be reported to their doctor or nurse (see "Breast cancer" below). In all cases of undiagnosed, persistent or recurring abnormal vaginal bleeding, adequate diagnostic measures, including endometrial sampling, should be undertaken to rule out malignancy. The benefits and risks of HRT should be carefully considered. HRT should be dosed at the lowest effective dose to relieve symptoms and for the shortest duration for control of symptoms.

Cardiovascular disorders.

Estrogen/ progestogen therapy has been associated with an increased risk of cardiovascular events such as myocardial infarction and stroke, as well as venous thrombosis and pulmonary embolism (venous thromboembolism or VTE). Should any of these occur or be suspected, estrogen/ progestogen therapy should be discontinued immediately.
Risk factors for arterial vascular disease (e.g. hypertension, diabetes mellitus, tobacco use, hypercholesterolaemia, and obesity) and/or venous thromboembolism (e.g. personal history or family history of VTE, obesity, and systemic lupus erythematosus) should be managed appropriately.

Coronary heart disease and stroke.

In the estrogen plus progestogen substudy of the Women's Health Initiative (WHI) study, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving conjugated equine estrogen (CEE) plus medroxyprogesterone acetate (MPA) compared to women receiving placebo (37 vs 30 per 10,000 women years). The increase in risk was observed in year one and persisted (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
In the same substudy of WHI, an increased risk of stroke was observed in women receiving estrogen plus progestogen compared to women receiving placebo (29 vs 21 per 10,000 women years). The increase in risk was observed after the first year and persisted. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age dependent, the overall risk of stroke in women who use HRT will increase with age (see Section 4.8 Adverse Effects (Undesirable Effects)).
In postmenopausal women with documented heart disease (n = 2763, average age 66.7 years) a controlled clinical trial of secondary prevention of cardiovascular disease (Heart and Estrogen/ progestin Replacement Study; HERS) treatment with CEE plus MPA demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CEE plus MPA did not reduce the overall rate of CHD events in postmenopausal women with established coronary heart disease. There were more CHD events in the estrogen/ progestogen treated group than in the placebo group in year 1, but not during the subsequent years. Two thousand three hundred and twenty one women from the original HERS trial agreed to participate in an open label extension of HERS, HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the estrogen/ progestogen treated group and the placebo group in HERS, HERS II, and overall.
A Cochrane meta-analysis including 19 trials with a total of 40,410 post-menopausal women found evidence that hormone therapy in both primary and secondary prevention conferred no protective effects for all-cause mortality, cardiovascular death, non-fatal myocardial infarction, angina, or re-vascularisation. There was an increased risk of stroke in those in the hormone therapy arm for primary prevention (RR 1.32; 95% CI 1.12 to 1.56). The absolute risk increase for stroke was 6 per 1000 women (number needed to treat for an additional harmful outcome (NNTH) = 165; mean length of follow-up: 4.21 years (range: 2.0 to 7.1)).
In a nested case control study of the UK-based General Practice Research Database which included data from 69,412 women: 4658 estradiol/dydrogesterone (E/D) users, 30,048 users of other MHT, and 34 706 women who never used MHT. The incidence rates of MI and thrombotic stroke in E/D users were 0.40 (95% confidence interval (CI) 0.18-0.76) and 0.27 (95% CI 0.10-0.58) per 1000 person-years, respectively. As compared to non-users of HRT, the adjusted relative risk estimates (odds ratios) in the nested case-control analysis for ED users or users of other HRT were 1.06 (95% CI 0.48-2.36) and 1.12 (95% CI 0.84-1.51) for MI and 0.50 (95% CI 0.21-1.22) and 1.18 (95% CI 0.94-1.48) for thrombotic stroke.

Venous thromboembolism (VTE).

In the estrogen plus progestogen substudy of WHI, a 2-fold greater rate of VTE, including deep venous thrombosis and pulmonary embolism, was observed in women receiving CEE + MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 women years in the estrogen plus progestogen treated group compared to 16 per 10,000 women years in the placebo group. The increase in VTE risk was observed during the first year and persisted (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
A Cochrane meta-analysis including 19 trials with a total of 40,410 post-menopausal women found an increased risk of venous thromboembolic events (RR 1.92, 95% CI 1.36 to 2.69), as were pulmonary emboli (RR 1.89, 95% CI 1.17 to 3.04) on hormone therapy relative to placebo. The absolute risk increased for venous thromboembolism 8 per 1000 women (NNTH = 118; mean length of follow-up: 5.95 years (range: 1.0 to 7.1)); and for pulmonary embolism 4 per 1000 (NNTH = 242; mean length of follow-up: 3.13 years (range: 1.0 to 7.1)).
Data from two large, nested case-control studies in a UK population of 80,396 with primary diagnosis of VTE (1998-2017) showed for oral MHT therapy compared with no use a significantly increased risk of venous thromboembolism (adjusted odds ratio 1.58, 95% confidence interval 1.52 to 1.64). The risk was increased for both, oestrogen only preparations (1.40, 1.32 to 1.48) and combined oestrogen-progestin preparations (1.73, 1.65 to 1.81). Estradiol had a lower risk than conjugated equine oestrogen for oestrogen only preparations (0.85, 0.76 to 0.95) and combined preparations (0.83, 0.76 to 0.91). Compared with no exposure, conjugated equine oestrogen plus medroxyprogesterone acetate had the highest risk (2.10, 1.92 to 2.31), and estradiol plus dydrogesterone had the lowest risk (1.18, 0.98 to 1.42). The risk non-significantly increased with higher doses of estradiol (E2): E2 ≤ 1 mg/dydrogesterone 1.12 (0.90 to 1.40) and E2 > 1 mg/dydrogesterone 1.34 (0.94 to 1.90). The risk of cyclical compared to continuous regimen of dydrogesterone was non-significantly higher (1.21, 0.95 to 1.53 compared to 1.13, 0.84 to 1.53).
Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients (see Section 4.3 Contraindications).
Generally recognised risk factors for VTE include: use of estrogens, older age, major surgery, prolonged immobilisation, obesity (BMI > 30 kg/m2), pregnancy/ postpartum period, systemic lupus erythematosus (SLE), and cancer. There is no consensus about the possible role of varicose veins in VTE.
As in all postoperative patients, prophylactic measures need to be considered to prevent VTE following surgery. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilisation. Treatment should not be restarted until the woman is completely mobilised.
In women with no personal history of VTE but with a close relative with a history of thrombosis at a young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening).
If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is 'severe' (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects) HRT is contraindicated.
Women already on chronic anticoagulant treatment require careful consideration of the benefit/ risk of use of HRT.
If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctor immediately they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

Malignant neoplasms.

Breast cancer. The overall evidence shows an increased risk of breast cancer in women taking combined estrogen/progestogen HRT or estrogen-only HRT, that is dependent on the duration of taking HRT.

Combined estrogen/progestogen therapy.

The randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and a meta-analysis of prospective epidemiological studies are consistent in finding an increased risk of breast cancer in women taking combined estrogen/progestogen for HRT that becomes apparent after about 3 (1-4) years (see Section 4.8 Adverse Effects (Undesirable Effects)).

Estrogen-only therapy.

The WHI trial found no increase in the risk of breast cancer in hysterectomised women using estrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is lower than that found in users of estrogen/progestogen combinations (see Section 4.8 Adverse Effects (Undesirable Effects)).
After a mean follow-up of 5.6 years, the WHI trial reported an increased risk of breast cancer in women who took estrogen plus progestogen. Results from a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more. In the meta-analysis, the risk of breast cancer with estrogen plus dydrogesterone was lower than that noted with other synthetic progestogens, although the meta-analysis only included a relatively small number of women on dydrogesterone. Less than 5 years of use of estrogen plus dydrogesterone was not associated with a statistically significant increased risk of breast cancer (RR 1.21; 95% CI 0.90 to 1.61). The risk, however, was increased with 5-14 years (RR 1.41; 95% CI 1.17 to 1.71) and ≥ 15 years of use of estrogen plus dydrogesterone (RR 2.23; 95% CI 1.32 to 3.26), although this appeared lower than that noted with other synthetic progestogens. The meta-analysis also noted that risk was reduced when progestogen was administered intermittently (10-14 days/month). During years 5-14 of use of an oestrogen-progestogen combination, the RR was greater for oestrogen plus daily progestogen than for oestrogen plus intermittent progestogen (which usually involved 10-14 days of progestogen per month); RR 2.30 (2.21-2.40) and RR 1.93 (1.84-2.01), respectively, heterogeneity p < 0.0001.
In the French E3N cohort study that assessed and compared the association between different HRT and breast cancer risk, during follow-up (mean duration 8.1 postmenopausal years), 2,354 cases of invasive breast cancer occurred among 80,377 postmenopausal women were reported. Compared with HRT never-use, the association of estrogen/progestogen combinations with breast cancer risk varied significantly according to the type of progestogen: the relative risk was 1.00 (0.83-1.22) for estrogen/progesterone, 1.16 (0.94-1.43) for estrogen/dydrogesterone, and 1.69 (1.50-1.91) for estrogen combined with other progestogens (which included MPA).
The use of estrogen plus progestogen has been reported to result in an increase in abnormal mammograms requiring further evaluation. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.
HRT, especially estrogen/ progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Endometrial cancer.

The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in nonusers, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with the use of estrogens for less than one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued.

Addition of a progestogen when a woman has not had a hysterectomy.

Studies of the addition of a progestogen for 10 or more days of a cycle of estrogen administration, or daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a precursor to endometrial cancer. There are, however, possible risks that may be associated with the use of progestogens with estrogens compared with estrogen alone regimens. These include a possible increased risk of breast cancer, adverse effects on lipoprotein metabolism (e.g. lowering HDL, raising LDL) and impairment of glucose tolerance. Clinical surveillance of all women taking estrogen/ progestogen combinations is important. Adequate diagnostic measures, including endometrial sampling when indicated, should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose.

Dementia.

In the Women's Health Initiative Memory Study (WHIMS), an ancillary study of WHI, a population of 4532 women aged 65 to 79 years was randomised to CEE plus MPA or placebo. A population of 2947 hysterectomised women, aged 65 to 79 years, was randomised to CEE alone or placebo. In the planned analysis, pooling the events in women receiving CEE alone or CEE plus MPA in comparison to those in women on placebo, the overall relative risk (RR) for probable dementia was 1.76 (95% CI 1.19-2.60). In the estrogen alone group, after an average follow-up of 5.2 years a RR of 1.49 (95% CI 0.83-2.66) for probable dementia was observed compared to placebo. In the estrogen plus progestogen group, after an average follow-up of 4 years, a RR of 2.05 (95% CI 1.21-3.48) for probable dementia was observed compared to placebo. Since this study was conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women (see Section 4.4 Special Warnings and Precautions for Use, Use in the elderly).

Gallbladder disease.

A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery in postmenopausal women receiving estrogens has been reported.

Hypercalcaemia.

Estrogen administration may lead to severe hypercalcaemia in patients with breast cancer and bone metastases. If hypercalcaemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.

Visual abnormalities.

Retinal vascular thrombosis has been reported in patients receiving estrogens. Discontinue medication pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilloedema or retinal vascular lesions, estrogens should be discontinued.

Elevated blood pressure.

In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens. In a large, randomised, placebo controlled clinical trial, a generalised effect of estrogen therapy on blood pressure was not seen. Blood pressure should be monitored at regular intervals with estrogen use.

Hypertriglyceridaemia.

In patients with pre-existing hypertriglyceridaemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications.

Impaired liver function and past history of cholestatic jaundice.

Estrogens may be poorly metabolised in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued.

Hypothyroidism.

Estrogen administration leads to increased thyroid binding globulin (TBG) levels, leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin). Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

Fluid retention.

Because estrogens/ progestogens may cause some degree of fluid retention, patients with conditions that might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.

Hypocalcaemia.

Estrogens should be used with caution in individuals with severe hypocalcaemia.

Ovarian cancer.

Ovarian cancer is much rarer than breast cancer. Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking estrogen only or combined estrogen/ progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping. Some other studies, including the WHI trial suggest that use of combined HRTs may be associated with a similar, or slightly smaller risk (see Section 4.8 Adverse Effects (Undesirable Effects)).

Exacerbation of endometriosis.

Endometriosis may be exacerbated with administration of estrogen therapy.

Exacerbation of other conditions.

Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine, porphyria, systemic lupus erythematosus, and hepatic haemangiomas and should be used with caution in women with these conditions.

Conditions which need supervision.

If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Femoston-Conti, in particular: leiomyoma (uterine fibroids) or endometriosis; risk factors for thromboembolic disorders; risk factors for estrogen dependent tumours e.g. 1st degree heredity for breast cancer; hypertension; liver disorders (e.g. liver adenoma); diabetes mellitus with or without vascular involvement; cholelithiasis; migraine or (severe) headache; systemic lupus erythematosus; a history of endometrial hyperplasia; epilepsy; asthma; otosclerosis.

Reasons for immediate withdrawal of therapy.

Therapy should be discontinued in case a contraindication is discovered and in the following situations: jaundice or deterioration in liver function; significant increase in blood pressure; new onset of migraine type headache, sudden partial or complete loss of vision, sudden onset of proptosis; pregnancy.

Bleeding patterns.

Breakthrough bleeding and spotting may occasionally occur during the first months of treatment. If breakthrough bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

Other conditions.

Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Femoston-Conti is increased.
Published literature has reported an increased risk of inflammatory bowel disease (ulcerative colitis and Crohn's disease) in association with HRT use.
Estrogens and progestogens (C19) can influence carbohydrate metabolism. This has not been observed with hormone replacement therapy involving natural estrogens.
Patients with rare hereditary problems of galactose intolerance, the total lactase deficiency or glucose/ galactose malabsorption should not take this medicine.
Femoston-Conti is not an oral contraceptive. Patients in the perimenopausal phase should be advised to use nonhormonal contraceptive methods.
Exogenous oestrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.

ALT elevations.

ALT elevations have been observed in studies of women treated for hepatitis C virus (HCV) infections with combination of anti-viral regimens and concomitant use of ethinylestradiol containing medications such as CHCs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in the elderly.

Of the total number of subjects in the estrogen plus progestogen substudy of the Women's Health Initiative study, 44% (n = 7320) were 65 years and over, while 6.6% (n = 1095) were 75 years and over (see Section 5.1 Pharmacodynamic Properties, Clinical trials). There was a higher incidence of stroke and invasive breast cancer in women 75 and over compared to women less than 75 years of age. In the Women's Health Initiative Memory Study (WHIMS), an ancillary study of WHI, a population of 4532 women aged 65 to 79 years was randomised to a continuous combined regimen of conjugated equine estrogens 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day or placebo. A population of 2947 hysterectomised women, aged 65 to 79 years, was randomised to conjugated equine estrogens (CEE 0.625 mg) alone or placebo. In the planned analysis, pooling the events in women receiving CEE or CEE plus MPA in comparison to those in women on placebo, the overall relative risk (RR) for probable dementia was 1.76 (95% CI 1.19-2.60). In the estrogen alone group, after an average follow-up of 5.2 years a RR of 1.49 (95% CI 0.83-2.66) for probable dementia was observed compared to placebo. In the estrogen plus progestogen group, after an average follow-up of 4 years, a RR of 2.05 (95% CI 1.21-3.48) for probable dementia was observed compared to placebo. Since this study was conducted in women aged 65 to 79 years, it is unknown whether these findings apply to younger postmenopausal women (see Section 4.4 Special Warnings and Precautions for Use, Dementia).
With respect to efficacy in the approved indications, there have not been sufficient numbers of geriatric patients involved in studies utilising estrogens and progestogens to determine whether those over 65 years of age differ from younger subjects in their response to estrogens and progestogens.

Paediatric use.

Femoston-Conti 1/5 is not recommended for use in children below age 18 due to insufficient data on safety and efficacy.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been performed.

The efficacy of estrogen and progestogens may be impaired.

The concomitant use of drugs known to induce drug metabolising enzymes, specifically P450 enzymes 2B6, 3A4, 3A5, 3A7, such as anticonvulsants (e.g. phenobarbital, carbamazepine, phenytoin) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz), may increase the metabolism of estrogen resulting in decreased estrogenic activity.
Ritonavir and nelfinavir, although known as strong inhibitors of CYP450 3A4, A5, A7, by contrast, exhibit inducing properties when used concomitantly with steroid hormones.
Clinically, an increased metabolism of estrogens and progestogens may lead to decreased effect and changes in the uterine bleeding profile.
Herbal preparations containing St John's wort (Hypericum perforatum) may induce the metabolism of estrogens and progestogens via the CYP450 3A4 pathway.

Interactions with HCV combination drug regimen.

During clinical trials with the HCV combination drug regimen ombitasvir/paritaprevir/ritonavir with and without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the combination drug regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir and also the regimen with glecaprevir/pibrentasvir (see Section 4.4 Special Warnings and Precautions for Use).

Estrogens might interfere with the metabolism of other drugs.

Estrogens may inhibit CYP450 drug metabolising enzymes via competitive inhibition. This is in particular to be considered for substances with a narrow therapeutic index, such as: tacrolimus and ciclosporin A (CYP450 3A4, 3A3); fentanyl (CYP450 3A4); theophylline (CYP450 1A2).
Clinically this may lead to a plasma increase of the affected substance up to toxic levels. Thus, careful drug monitoring for an extended period of time might be necessary and a dosage decrease of tacrolimus, fentanyl, ciclosporin A and theophylline may be necessary.

Effect of HRT with oestrogens on other medicinal products.

Hormone contraceptives containing oestrogens have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control. Although the potential interaction between hormone replacement therapy and lamotrigine has not been studied, it is expected that a similar interaction exists, which may lead to a reduction in seizure control among women taking both medicinal products together.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category B3)
Femoston-Conti is contraindicated during pregnancy. If pregnancy occurs during medication with Femoston-Conti, treatment should be withdrawn immediately.
In animal studies, maternal administration of high doses of estradiol and dydrogesterone (as individual agents) produced urogenital malformations in the offspring. The clinical relevance of these findings is unclear.
The results of most epidemiological studies to date relevant to inadvertent fetal exposure to combinations of estrogens with progestogens indicate no obvious teratogenic or fetotoxic effect. However, there are no adequate data from the use of estradiol/ dydrogesterone in pregnant women.
Estrogen administration to nursing mothers has been shown to decrease the quantity and quality of milk. Detectable amounts of estrogens and progestogens have been found in the milk of lactating mothers receiving these compounds, but the effects on the breastfed infant have not been determined. Hormones, such as estrogens and progestogens should not be taken by nursing mothers.

4.7 Effects on Ability to Drive and Use Machines

Femoston-Conti 1/5 has no or negligible influence on the ability to drive and use machines.

Note.

Femoston-Conti does not cause drowsiness.

4.8 Adverse Effects (Undesirable Effects)

The most commonly reported adverse drug reactions of patients treated with estradiol/ dydrogesterone in clinical trials are headache, abdominal pain, breast pain/ tenderness and back pain.
Side effects data available from the premarketing clinical trial program are tabulated at a frequency of 1% or more, according to each body system and in descending order of frequency. See Table 1.
As expected, side effects, if they occur, are more common in the first months of treatment.

Treatment emergent adverse reactions with Femoston-Conti.

Very common (> 10%).

Gastrointestinal.

Abdominal pain, nausea.

Reproductive, female.

Breast pain, dysmenorrhoea.

Body as a whole, general.

Headache.
Common (1-10%).

Body as a whole, general.

Oedema, weight change.

Reproductive, female.

Intermittent bleeding/ spotting.
Uncommon (0.1-1%).

Reproductive, female.

Ovarian cyst.

Breast cancer.

An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestogen therapy for more than 5 years.
The increased risk in users of oestrogen-only therapy is lower than that seen in users of oestrogen-progestogen combinations.
The level of risk is dependent on the duration of use (see Section 4.4 Special Warnings and Precautions for Use).
The absolute risk estimations based on results from the largest meta-analysis of prospective epidemiological studies and the WHI trial are presented in Tables 2, 3, and 4.
See Section 4.4 Special Warnings and Precautions for Use, Malignant neoplasms, Breast cancer.

Endometrial cancer.

Postmenopausal women with a uterus.

The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT.
In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed estrogens (see Section 4.4 Special Warnings and Precautions for Use). Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.
Adding a progestogen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase the risk of endometrial cancer (RR of 1.0 (0.8-1.2)).

Ovarian cancer.

Use of estrogen only or combined estrogen/ progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see Section 4.4 Special Warnings and Precautions for Use). A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (1.43, 95% CI 1.31-1.56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per 2000 users. In women aged 50-54 who are not taking HRT, about 2 women in 2000 will be diagnosed with ovarian cancer over a 5 year period.

Risk of venous thromboembolism.

HRT is associated with a 1.3-3-fold increased relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of using HRT (see Section 4.4 Special Warnings and Precautions for Use). Results of the WHI studies are presented in Table 5.

Risk of coronary artery disease.

The risk of coronary artery disease is slightly increased in users of combined estrogen/ progestogen HRT over the age of 60 (see Section 4.4 Special Warnings and Precautions for Use).

Risk of ischaemic stroke.

The use of estrogen/ progestogen therapy is associated with an up to 1.5-fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT. This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age dependent, the overall risk of stroke in women who use HRT will increase with age (see Section 4.4 Special Warnings and Precautions for Use). See Table 6.

Other adverse effects.

Other adverse reactions have been reported in association with estrogen/ progestogen treatment (including estradiol/ dydrogesterone):

Neoplasms benign, malignant and unspecified.

Estrogen dependent neoplasms both benign and malignant, e.g. endometrial cancer, ovarian cancer. Increase in size of progestogen dependent neoplasms, e.g. meningioma.

Blood and lymphatic system disorders.

Haemolytic anaemia (very rare).

Immune system disorders.

Systemic lupus erythematosus.

Metabolism and nutrition disorders.

Hypertriglyceridemia.

Nervous system disorders.

Probable dementia, chorea (very rare), exacerbation of epilepsy.

Eye disorders.

Intolerance to contact lenses, steepening of corneal curvature (rare).

Reproductive system and breast disorders.

Fibrocystic breast changes, change in cervical erosion (uncommon).

Vascular disorders.

Arterial thromboembolism, stroke (very rare).

Gastrointestinal disorders.

Pancreatitis (in women with pre-existing hypertriglyceridemia).

Skin and subcutaneous tissue disorders.

Chloasma or melasma, which may persist when drug is discontinued (very rare), erythema multiforme (very rare), erythema nodosum (very rare).

Musculoskeletal and connective tissue disorders.

Leg cramps (common).

Congenital and familial/ genetic disorders.

Aggravation of porphyria (very rare).

Investigations.

Total thyroid hormones increased.

Renal and urinary disorders.

Urinary incontinence.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

No acute serious medical effects have been reported in association with an overdosage of either estradiol or dydrogesterone. Possible symptoms following overdosage are similar to the adverse reactions. Symptoms such as nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/fatigue, and withdrawal bleeding could occur in cases of overdosing. It is unlikely that any specific symptomatic treatment will be necessary. There are no specific therapeutic recommendations for the management of overdosage. In the event of a large overdose treatment should be symptomatic. For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The estrogenic agent, estradiol, is chemically and biologically identical to endogenous human estradiol and has pharmacological actions similar to the physiological effects of the endogenous hormone. Estradiol is the primary estrogen and the most active of the ovarian hormones. The Femoston-Conti estradiol preparation relieves the vasomotor symptoms arising from the decrease in the ovarian estrogen production, resulting from natural or artificially induced menopause. In addition to relieving or eliminating these symptoms, estrogen replacement therapy has also been demonstrated to retard or halt postmenopausal bone mass loss (osteoporosis) and to play an important role in fat metabolism.
Dydrogesterone given orally has progestational effects similar to parenterally administered progesterone. Unopposed estrogen treatment has been reported to increase the risk of endometrial carcinoma. The inclusion of dydrogesterone induces a secretory endometrium in an estrogen-primed uterus. Dydrogesterone does not cause androgenic side effects.
In the context of continuous combined HRT, dydrogesterone produces an atrophic endometrium and amenorrhoea, thereby providing protection against estrogen induced increased risk of endometrial hyperplasia and/or carcinoma.

Clinical trials.

The efficacy of estradiol in relieving menopausal symptoms was demonstrated in a one-year, double blind, randomised study, using 1 mg estradiol continuously combined with 5 mg to 20 mg dydrogesterone (n = 318), and in a one year open label study investigating the effects of 1 mg estradiol continuously combined with 2.5 mg dydrogesterone (n = 165). In both studies, relief of menopausal symptoms was a secondary outcome. In comparison with baseline, a considerable decrease in frequency of hot flushes was observed, with majority of the effect noted by the first observation point at 6 weeks and the effect maintained to the end of the study. Both studies also demonstrated a decrease in frequency of night sweats, sweating attacks and sleeplessness. The dose and duration of dydrogesterone had no influence on the efficacy of estradiol in relieving menopausal symptoms.
Endometrial protection was evaluated in studies involving 1103 postmenopausal women. Protection against endometrial stimulation was investigated in two studies (n = 310) using 2 mg estradiol combined with 2.5, 5, 10 and 15 mg dydrogesterone. Adequacy of the progestational response (absence of endometrial hyperplasia) after 6 months treatment was determined to be greater than 99% for all doses of dydrogesterone tested. A proliferative endometrium was reported in 7% of women, the majority being on 2.5 mg dydrogesterone. Protection against endometrial stimulation was also investigated in 3 studies using 1 mg estradiol continuously combine with 2.5, 5, 10 and 20 mg dydrogesterone (n = 650). As with the 2 mg estradiol dose the adequacy of the progestational response (absence of endometrial hyperplasia) after 12 months treatment was determined to be greater than 99% for all doses of dydrogesterone tested. Endometrial proliferation was reported in 3% of women, majority being on 2.5 mg dydrogesterone. The dose selected to oppose 1 mg estradiol in a continuous combined regimen was therefore 5 mg, which was associated with a hyperplasia rate of 0.6% and a proliferation rate of 2%.
Data from a study on postmenopausal women (n = 214), who had not received HRT previously, in which 1 mg estradiol was combined daily with either 5, 10 or 20 mg dydrogesterone, showed a statistically significant (p < 0.001) increase in bone mineral density (BMD) at the lumbar spine (3.6%) and femoral neck (1.2%) after one year. Irregular bleeding was reduced by about 50% on 1 mg estradiol, amenorrhoea rates doubled at 6 months and early withdrawals due to vaginal bleeding were halved. By one year, over 80% of women on 1 mg estradiol were amenorrhoeic.

Bone mineral density effects.

In a two-year, double-blind, placebo-controlled study in postmenopausal women the effects of 1 mg and 2 mg estradiol sequentially combined with 5-20 mg dydrogesterone was investigated. A clinically relevant and statistically significant (p < 0.001) mean increase in BMD was observed in the lumbar spine and femoral neck after 1 and 2 years, in both the 1 mg and 2 mg groups of the evaluable patient sample (n = 409). At 2 years, the mean increases in BMD at the femoral neck were 2.7% (± 4.24) with 1 mg estradiol and 2.5% (± 4.99) with 2 mg estradiol, and the increase in the lumbar spine was 5.2% (± 3.76) with 1 mg estradiol and 6.7% (± 3.83) with 2 mg estradiol. Both increases were statistically significant from baseline, but not from each other.

Lipid effects.

A one-year double-blind study in postmenopausal women (n = 304) investigated the effects of 1 mg estradiol combined with daily dydrogesterone 5-20 mg on serum lipids. In all groups, over 52 weeks, HDL levels increased (+5%), LDL and total cholesterol levels both decreased (-9% and -6% respectively), and lipoprotein(a) levels also decreased (-12.5%). There were no significant differences between the three dosages. The favourable changes in lipid profiles seen with sequential Femoston are also seen with Femoston-Conti.
As reported in observational studies, an improvement of the lipid profile may be a factor contributing to the beneficial effect of estrogens in reducing the risk of coronary heart disease in postmenopausal women. However, the long-term effects of these changes on the cardiovascular system are unknown.

Women's Health Initiative studies.

A substudy of the Women's Health Initiative (WHI) enrolled 16,608 predominantly healthy postmenopausal women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic) to assess the risks and benefits of the use of a continuous combined regimen of conjugated equine estrogens (CEE) 0.625 mg plus medroxyprogesterone acetate (MPA) 2.5 mg per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A "global index" included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CEE plus MPA on menopausal symptoms. The estrogen plus progestogen substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the "global index". Results are presented in Table 7.
For those outcomes included in the "global index", the absolute excess risks per 10,000 women years in the group treated with CEE + MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the "global index" was 19 per 10,000 women years. There was no difference between the groups in terms of all cause mortality (see Boxed Warnings; Section 4.4 Special Warnings and Precautions for Use).

Women's Health Initiative Memory Study.

The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CEE plus MPA on the incidence of probable dementia (primary outcome) compared with placebo.
After an average follow-up of 4 years, 40 women in the estrogen/ progestogen group (45 per 10,000 women years) and 21 in the placebo group (22 per 10,000 women years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. (See Section 4.4 Special Warnings and Precautions for Use, Dementia, Use in the elderly).

Guidelines on menopause and MHT.

The International Menopause Society (IMS) and the British Menopause Society (BMS) provide recommendations on MHT in menopausal women. Their Recommendations and Consensus Statements include assessments of the long-term risks of thrombosis and breast cancer associated with dydrogesterone compared to other progestogens. For full details, please refer to the most recent guidance provided by the IMS and the BMS.
Other resources available to clinicians include a Joint Statement from these organisations, BMS, IMS, European Menopause and Andropause Society (EMAS), Royal College of Obstetricians and Gynaecologists (RCOG) and Australasian Menopause Society (AMS) on menopausal hormone therapy (MHT) and breast cancer risk in response to EMA Pharmacovigilance Risk Assessment Committee recommendations (May 2020).

5.2 Pharmacokinetic Properties

Micronised estradiol is rapidly and efficiently absorbed from the gastrointestinal tract. Following oral administration, estradiol is extensively metabolised. The major unconjugated and conjugated metabolites are estrone and estrone sulfate. These metabolites may contribute to the estrogenic activity, either directly or following conversion to estradiol. Conjugates of the various estrogens and their metabolites are excreted in the urine, whilst unconjugated metabolites appear in the faeces. Estrogens are also secreted in the milk of nursing mothers.
Following oral administration, dydrogesterone is completely metabolised, with an average 63% of the dose excreted into the urine. Excretion is complete within 72 hours. The major metabolite of dydrogesterone is 20α-dihydrodydrogesterone (DHD), excreted predominantly in the urine as the glucuronic acid conjugate. A common feature of all metabolites of dydrogesterone characterised is the retention of the 4,6 diene-3-one configuration of the parent compound and the absence of 17α-hydroxylation. This accounts for the lack of estrogenic and androgenic effects of dydrogesterone. Plasma concentrations of DHD following oral administration of dydrogesterone are substantially higher in comparison to the parent drug. The AUC and Cmax ratios of DHD to dydrogesterone are in the order of 40 and 25, respectively. The Tmax values of dydrogesterone and DHD vary between 0.5 and 2.5 hours. The mean terminal half-lives of dydrogesterone and DHD vary between 5 to 7 and 14 to 17 hours, respectively. Unlike progesterone, dydrogesterone is not excreted in urine as pregnanediol. It therefore remains possible to analyse endogenous progesterone production based on pregnanediol excretion.
No clinically relevant pharmacokinetic interactions occur between estradiol and dydrogesterone.

5.3 Preclinical Safety Data

Genotoxicity.

Genotoxicity assays with estradiol have shown no changes in the incidence of sister chromatid exchanges, but have shown increased frequency of gene mutation in transformed mouse cells in vitro, chromosomal aberrations in Chinese hamster ovary cells in vitro, and increased aneuploidy in Syrian hamster embryo cells and cultured human fibroblasts in vitro.
Dydrogesterone did not exhibit any evidence of genotoxicity in gene mutation studies in bacteria or in tests for clastogenic effects in mammalian cells in vitro or in vivo.

Carcinogenicity.

Supraphysiological doses of estradiol have been associated with the induction of tumours in estrogen dependent target organs in all rodent species tested. The relevance of these findings with respect to humans has not been established. Unopposed estrogen therapy is associated with an increased incidence of endometrial carcinoma, particularly with prolonged use. Concurrent progestogen therapy for a minimum of 12 to 14 days reduces the risk of endometrial hyperplasia.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, hypromellose, maize starch, colloidal anhydrous silica, magnesium stearate and Opadry complete film coating system OY-8734 orange (ARTG PI No. 4164).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 30°C.

6.5 Nature and Contents of Container

Available in PVC/Al blister packs of 7, 28, 56 or 84 tablets.
Some pack sizes may not be marketed.

Australian register of therapeutic goods (ARTG).

AUST R 78654 - Femoston-Conti tablet blister pack.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking it to your local pharmacy.

6.7 Physicochemical Properties

Chemical structure.

Estradiol hemihydrate.

Chemical Name: estra-1,3,5(10)- triene-3, 17β-diol hemihydrate.
C18H24O2.½H2O. MW: 281.4.
It is a white or almost white, crystalline powder or colourless crystals. Melting point: approximately 175°C to 180°C. Solubility: practically insoluble in water, soluble in acetone, sparingly soluble in ethanol (96 per cent), slightly soluble in methylene chloride.

Dydrogesterone.

Chemical Name: 9β, 10α-pregna-4, 6 diene-3, 20 dione.
C21H28O2. MW: 312.5.
It is a white to pale yellow crystalline powder; odourless to almost odourless. Melting point: approximately 167°C to 171°C. Solubility: practically insoluble in water; freely soluble in chloroform; soluble in acetone; slightly soluble in ethanol (96%) and in methanol; and slightly in ether and in fixed oils.

CAS number.

Estradiol hemihydrate: 35380-71-3.
Dydrogesterone: 152-62-5.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription Only Medicine).

Summary Table of Changes